The overall aim of this application is to determine the mechanism(s) by which common genetic variation in TCF7L2, recently associated with type 2 diabetes alters glucose metabolism. We wish to do so in order to develop rational approaches for the prevention and treatment of diabetes. Type 2 diabetes is a common metabolic disorder that arises out of a complex interaction between genes and the environment. It is proceeded by pre-diabetes where affected subjects have elevated fasting or postprandial glucose concentrations but do not fulfill the criteria for the diagnosis of diabetes. Individuals with prediabetes are at high risk of progression to diabetes. Analysis of participants in the diabetes prevention program has also independently confirmed that common variants in TCF7L2 are associated with increased risk of diabetes among persons with impaired glucose tolerance. Although there is some understanding as to how variation in KCNJ11 and PPARG alters glucose metabolism, little is known about how TCF7L2 alters glucose homeostasis. TCF7L2 is a transcription factor that may modulate signaling pathways necessary for blood glucose homeostasis. It has been shown that individuals with the disease-associated variant(s) of this gene secrete less insulin during an oral glucose tolerance test (OGTT). However, despite the reproducible association of this genetic locus with type 2 diabetes, there is very little knowledge of how variation in this locus affects glucose homeostasis in humans with and without impaired fasting glucose and / or impaired glucose tolerance and ultimately how this gene contributes to the development of diabetes. The product of TCF7L2 is an important constituent of the wnt-signaling cascade that regulates proglucagon gene expression. The protein product of proglucagon is differentially processed in intestinal L cells to produce glucagon-like peptide-1 (GLP-1), an incretin hormone that is a potent insulin secretagogue and defective secretion of GLP-1 has been associated with type 2 diabetes and impaired glucose tolerance. The ability to predict diabetes development will allow targeted prevention strategies. It has been shown that common genetic variation in TCF7L2 predisposes to diabetes. Understanding the effect of this gene on glucose metabolism and GLP-1 secretion will immeasurably increase our ability to target prevention strategies to predisposed individuals.